tbuckley/cabot-search huggingface dataset:
Abstract 12634: A Novel <i>in-vitro</i> Patient-Specific Re-Engineered Cardiomyocyte Model of Multifocal Ectopic Purkinje-Related Premature Contractions
Authors: Xiaozhi Gao, Dan Ye, Wei Zhou, Samantha K Hamrick, Changsung Kim, David J Tester, John Giudicessi, Michael J Ackerman
Journal: Circulation (2022)

Introduction: Multifocal ectopic Purkinje-related premature contractions (MEPPC), the most recent addition to the spectrum of SCN5A -mediated cardiac channelopathies, is characterized by frequent premature ventricular complexes (PVCs) originating from the Purkinje system, atrial arrhythmias, and a predilection for PVC-mediated dilated cardiomyopathy. Hypothesis: To investigate the electrophysiology phenotype of MEPPC in a novel, patient-specific, re-engineered cardiomyocyte model. Methods: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from a 27-year-old male with a history of frequent, multifocal PVCs and atrial tachycardia, positive for a putative MEPPC-causative SCN5A variant (p.Q419P). A CRISPR-Cas9 Q419P variant-corrected isogenic control (IC) was created to establish the normalized electrophysiology recordings for that MEPPC model. The standard whole-cell patch clamp technique was used to measure Q419P-SCN5A- and IC-derived NaV1.5 sodium currents using voltage clamp configuration. In addition, action potential duration (APD) of the iPSC-CMs were measured using FluoVolt optical voltage-sensing dye. Results: Analysis of the current-voltage relationship revealed that neither peak sodium current densities nor late inward sodium current were impacted by Q419P-SCN5A. However, Q419P-SCN5A significantly right-shifted the V 1/2 in inactivation by 8.3 mV from -81.1±1.7 mV (IC, n=5) to -72.8±0.2 mV (Q419P-SCN5A, n=6, p&lt;0.05 vs. IC) and left-shifted the V 1/2 in activation by -4.1 mV from -39.5±0.3 mV (IC, n=5) to -43.6±0.9 mV (Q419P-SCN5A, n=6, p&lt;0.05 vs. IC) leading to a larger hyperpolarized window current. Optical APD90 measurement revealed no difference between the Q419P-containing (476 ± 23 ms) and the IC (474 ± 46 ms, p=0.867) cardiomyocytes. Conclusions: This is the first in-vitro disease model of MEPPC using patient-specific, re-engineered heart cells. Consistent with the findings in the non-cardiac HEK cell system, this MEPPC-causative variant contributes to increased window current in cardiomyocytes without affecting the cardiac APD. This novel cardiac cell model for MEPPC may facilitate new insights into the pathobiology of MEPPC and enable the testing of novel therapies for it.
Abstract 11755: Burden and Impact of Prediabetes on the Risk of Acute Myocardial Infarction and Subsequent Adverse Cardiovascular Outcomes in Smokers: A National Inpatient Sample Analysis, 2019
Authors: Advait Vasavada, Kshitij Mahajan, Syed Mohammad Moosi Raza, Swapnil Surpur, ananth vallabh guddeti, Mani Chandan Reddy Patlolla, Ehrima Fatima, Zarna Bambhroliya, Paul Gbemudu, Rupak Desai
Journal: Circulation (2022)

Background: The burden of prediabetes (pDM) in smokers remains unknown. We aimed to analyze the burden and impact of prediabetes on AMI [Type 1/Type 2] hospitalizations in smokers and outcomes using a nationally representative sample. Methods: We queried the National Inpatient Sample (2019) to identify AMI-related hospitalizations in adult non-diabetic smokers with vs without pDM using ICD-10 codes. Demographics, comorbidities, and outcomes including major cardiovascular and cerebrovascular adverse events (MACCE) were compared between two cohorts. Results: Overall prevalence of pDM in hospitalized non-diabetic smokers in 2019 was 1.2% (46770/3880640). AMI cohort with pDM often had males (59.4% vs 54.6%), blacks (23 vs 17.7%), Hispanics (8.7 vs 6.4%), Asian/Pacific Islanders (2.7 vs 1%), patients from higher-income quartile (16.4 vs 12.6%), and higher rates of modifiable CVD risk factors. Adjusted multivariable analysis revealed higher risk of overall (aOR 1.73 [1.60-1.88]), T1MI (1.86 [1.70-2.03]) and T2MI (OR 1.39 [1.16-1.67]). The risk of overall AMI was 1.73 times higher in patients with vs. without prediabetes, which was comparable in male (aOR 1.73) and female (aOR 1.72) smokers, however, female smokers with prediabetes had higher T2MI risk (aOR F:1.55, M:1.30) vs. males. Black smokers with prediabetes have the highest risk of overall (aOR 1.85), T1MI (aOR 2.03) and T2MI (aOR 1.77). Among Hispanics, prediabetes increased the risk of overall (aOR 1.69) and T1MI (aOR 1.92) but not T2MI. Prediabetes increased the risk of T1MI (aOR 1.74) in Asians without any association with overall or T2MI [Table 1]. Conclusions: Prediabetes independently increased the risk of overall AMI/T1MI/T2MI-related hospitalizations in non-diabetic smokers. Black smokers with prediabetes had the highest risk of AMI, T1MI and T2MI, and females had a higher risk of T2MI. This highlights the need for a tailored management of CVD risk by sex and race among smokers with prediabetes. .
Abstract 11589: Total Artificial Heart Placement in a Case of Recurrent Ventricular Tachycardia Storm
Authors: Brandon H Schwartz, Breanna Hansen, Paul Marano, Robert Cole
Journal: Circulation (2022)

Background: Electrical storm is defined as three or more episodes of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) within a 24-hour period requiring termination by cardioversion, anti-tachycardia pacing (ATP) or defibrillation. It can be a particularly challenging syndrome to treat when refractory to standard of care therapies, which include antiarrhythmics, sedation, and ablation. We present a case of refractory electrical storm requiring total artificial heart placement (TAH) as a bridge to transplant. Case: A 65-year-old male with a history of idiopathic non-ischemic cardiomyopathy presented with VF arrest. After return of spontaneous circulation, he was admitted to the cardiac intensive care unit. Implantable cardioverter defibrillator (ICD) interrogation showed 38 shocks delivered over the prior two-week period. Coronary angiography showed no obstructive coronary disease and an intraaortic balloon pump (IABP) was placed for cardiogenic shock. He was intubated and sedated on fentanyl and propofol. He continued to have episodes of VT despite treatment with lidocaine, procainamide, and amiodarone drips. Further trials of paralysis and left stellate ganglion nerve block did not suppress his VT. Since the patient was refractory to all prior interventions, was deemed too unstable for VT ablation, and had a prolonged anticipated wait time for heart transplant, he underwent TAH placement as a bridge to heart transplant. He recovered well and eventually underwent successful heart transplant. Discussion: Management of electrical storm requires a stepwise approach including administration of antiarrhythmics, sedation, mechanical hemodynamic support, and catheter ablation. Our patient had incessant VT despite exhaustive medical and supportive therapies, but was too unstable to undergo VT ablation. In cases of refractory VT storm, definitive treatment with heart transplantation must be considered, but bridging patients to transplant poses a challenge. Our patient underwent TAH placement and was successfully stabilized prior to transplant. In centers with this capability, TAH should be recognized as a legitimate option in the pathway for VT, particularly with a long anticipated wait time for heart transplant.
Abstract 11789: Exosomes Released by Human Cardiac Fibroblasts Promote the Maturation of Human Induced-Pluripotent Stem Cells Derived Cardiomyocyte via AMPK Signal Pathway
Authors: Kele Qin, Xun Wu, Kun Xiang, Jinfu Yang, Chengming Fan
Journal: Circulation (2022)

Background: Human induced-pluripotent stem cell derived cardiomyocytes (hiPS-CMs) is phenotypically less matured than adult cardiomyocytes. The aim of this study was to explore the potential mechanism by which human cardiac fibroblast-derived exosomes (hc-FB-EXOs) enhance the maturation of hiPS-CMs. Method: Exosomes were extracted from human cardiac fibroblasts (hc-FBs) which were cultured with exosome-free FBS medium. The cultured hiPS-CMs were randomly devided into two groups: co-culture with (EXO) and without (NC) hc-FB-EXOs. The morphology of hiPS-CMs was assessed via immunostaining. Mitochondrial functions assay were measured by Seahorse XF. Potential mechanism was assessed via mRNA-Seq, real-time PCR and western blot. Results: Morphologically, the cells treated in EXO group was significantly larger than the in NC group in terms of cell area and sarcomere length (Panel A). In cellular metabolism, the mitochondrial oxygen consumption rate of EXO group was significantly higher than that of NC group, including basal respiration, proton leak, maximal respiration and spare respiratory capacity (Panel B). The expression of cardiac Troponin I (cTnI), Myosin Heavy Chain 7 (MYH7), Cyclin Dependent Kinase Inhibitor 2C (CDKN2C or p18), phospho-WEE1 and CAV3 (caveolin3) were significant higher, while the expression of of Myosin Heavy Chain 6 (MYH6) was significant lower in EXO group than in NC group (Panel C). Furthermore, qPCR showed that TNNI1, TNNT2, TNNI3/TNNI1, total titin, N2B, MYH7, LPL, ND1, N2BA, and MYH6 were significantly upregulated in EXO group compared with the NC group. Furthermore, western blot validation of RNA-Seq data confirmed that significantly upregulated of phospho-AMPK and downregulated of ACC1 and SCD1 were detected in EXO group compared with the NC group (Panel D). Conclusion: hc-FB-EXOs could significantly facilitate maturation of hiPS-CMs via the phosphorylation of AMPK.
Abstract 12076: Longitudinal Echocardiographic Analysis of Aortic Valve Stenosis Progression
Authors: Jay Khambhati, Varsha K Tanguturi, Chen Chen, Marc Allard-Ratick, Paris J Jamiel, Michael H Picard, Dhaval Kolte, Evin Yucel, Judy Hung, Jonathan Passeri, Nathaniel Langer, Sammy Elmariah
Journal: Circulation (2022)

Introduction: Despite its high prevalence, the rate of progression of aortic valve stenosis (AS) remains incompletely characterized and assumed to be constant across the spectrum of AS severity. Previous studies involve limited number of patients, short follow-up, and focused on more severe stages of AS. Hypothesis: The annual rate of AS progression as defined by aortic valve mean gradient (AVMG) increases in magnitude as AS class severity increases. Methods: The study cohort included adult patients with native AS from the MGH echocardiography database from 1990 to 2020. Patients were included if AVMG was reported in at least two echocardiograms in mild, moderate, or severe AS stages. Generalized linear mixed models were employed to simultaneously model fixed effects and random effects stratified by AS severity grade. Multivariable models included age, sex, race, dyslipidemia, DM2, kidney disease, LVEF, moderate/severe AI, and AV morphology. A linear model identified risk factors for rapid progression in severe AS. Results: In 8,848 patients with 29,513 echocardiograms, baseline mean gradient for mild, moderate, and severe AS was 7.0, 20.9, and 43.0 mmHg, respectively. The annual rate of progression in mild, moderate, and severe AS was found to be 0.3, 1.0, and 4.0 mmHg/year. Female gender and white race increased the rate of AVMG by 0.57mmHg/year and 1.05mmHg/year. Conclusions: The progression of AS accelerates with worsening severity of AS. The rate of AVMG progression in severe AS is similar to historically accepted values, but rates are slower for mild and moderate AS. Female gender and white race may be associated with faster progression in severe AS.
Abstract 11197: Gender Differences and Temporal Trends in Clinical Characteristics and Use of Myocardial Scintigraphy in Evaluation of Stable CAD
Authors: Suvasini Lakshmanan, Paolo Frumento, Assuero Giorgetti, Stefano Dalmiani, Alessia Gimelli
Journal: Circulation (2022)

Introduction: Data on temporal and gender differences in referral patterns and clinical characteristics of patients referred for myocardial scintigraphy for suspected coronary artery disease (CAD), is lacking. Furthermore, the differential impact of COVID-19 pandemic on gender differences in referrals and clinical risk profile of referred patients is not known. Methods: This is a cross-sectional observational single center study of patients evaluated across 3 yearly time intervals in 2000, 2010 and 2020. We evaluated 2,615 patients (68% women) with mean age 65.9 years, who were referred for stress/rest myocardial scintigraphy. Trends in clinical characteristics and test results were compared in women and men across these intervals. Results: Men were more likely to be referred for testing than women, however there was a consistent increase in proportion of women referred over time, including the time of COVID pandemic in 2020. Men were more likely to present with typical symptoms, compared to women. Among women, there is a significant increase in prevalence of active smoking and a decrease in age at presentation and hypertension, over time (p&lt;0.05). Among men, there was a significant decrease in history of previous MI, with no change in other risk factors over time. Across time intervals, in both men and women, there was a significant increase in EF (Ejection Fraction) and decrease in presence of ischemic myocardium at risk, identified by semi-quantitative scores including summed rest score (SRS), summed stress score (SSS) at rest (p&lt;0.05). Conclusions: There are gender differences in proportion of men and women who are referred for stress testing, for evaluation of stable CAD. There was a substantial change in risk of inducible myocardial ischemia among male and female patients with known or suspected CAD. Our findings are relevant to understand the implications of gender differences on risk assessment and diagnostic accuracy in known or suspected CAD, over time.
Abstract 12413: Type 2 Diabetes Mellitus and Congestive Heart Failure in Women Are Mutually Independent Predictors of Non-alcoholic Fatty Liver Disease
Authors: Maximilian Maechler, Lukas Sprenger, Arthur Mader, Barbara Larcher, Alexander Vonbank, Andreas Leiherer, Axel Muendlein, Heinz Drexel, Christoph H Saely
Journal: Circulation (2022)

Introduction: Non-alcoholic fatty liver disease (NAFLD) is associated with both type 2 diabetes mellitus (T2DM) and congestive heart failure (CHF), and T2DM is highly prevalent in CHF patients, in particular among women. However, the single and joint associations of T2DM and CHF with NAFLD in women have not been investigated yet. Hypothesis: We hypothesize that congestive heart failure and T2DM are independent predictors of NAFLD in women. Methods: We investigated 76 female patients with CHF and 321 female controls who did not have signs or symptoms of CHF and in whom significant coronary artery disease was ruled out angiographically. The presence of NAFLD was determined using the validated fatty liver index (FLI). Results: The prevalence of T2DM was 39.5% in women with CHF and 22.1% in controls (p=0.002). FLI values and prevalence rates of NAFLD (FLI≥60) in non-CHF women without T2DM were 43±28 and 31.6%, respectively. They were significantly higher in non-CHF, but T2DM patients (65±28, p&lt;0.001 and 64.8%, p&lt;0.001, respectively), in CHF patients without T2DM (67±25, p&lt;0.001 and 63.0%, p=0.002, respectively) and in CHF patients with T2DM (66±31, p&lt;0.001 and 66.7%, p&lt;0.001, respectively). In multivariate analysis of covariance, T2DM and CHF proved to be mutually independent predictors of FLI after adjustment for age, sex, BMI, LDL-C, history of smoking and hypertension and use of statins (F=7.25; p=0.007 and F=46.89; p&lt;0.001, respectively); concordantly, T2DM and CHF independently predicted the presence of NAFLD in logistic regression analyses, with adjusted odds ratios of 3.22 [1.38-7.50]; p=0.007 and 21.71 [6.58-71.59]; p&lt;0.001, respectively. Conclusions: We conclude that CHF and T2DM are mutually independent predictors of NAFLD in women.
Abstract 12420: Orally Inhaled Flecainide for the Conversion of Recent-Onset, Symptomatic Atrial Fibrillation to Sinus Rhythm: Final Results From the Phase 2 Instant Trial
Authors: Alan J Camm, Harry Crijns, Arif Elvan, Ype Tuininga, Erik Badings, Aaf Kuijper, Jonas de Jong, Mark Lee, Dirk Schellings, Isabelle C Van Gelder, Jeremy N Ruskin, Peter R Kowey, Christopher Dufton, Jean Maupas, Luiz Belardinelli
Journal: Circulation (2022)

Introduction: The INSTANT trial was a multicenter, open-label, single-arm study of flecainide acetate oral inhalation solution (FlecIH) for acute conversion of recent-onset, symptomatic atrial fibrillation (AF) to sinus rhythm (SR). The initial dose-ranging stage of the trial established safety and feasibility, while showing a dose- and concentration-dependent increase in efficacy (dose range: 30-120 mg); the highest dose was selected for this evaluation. Methods: Patients with symptomatic paroxysmal AF (≤ 48 hours) self-administered 120 mg FlecIH over 8 minutes in a monitored setting using a breath-actuated nebulizer and were continuously monitored for 90 minutes using a 12-lead Holter. Symptoms, vital signs and adverse events were recorded. Safety analyses included all patients who received 120 mg FlecIH (N=98). Efficacy analyses were performed on a modified intention to treat population (N=81) that excluded patients with systemic flecainide present prior to dosing with study drug. Results: The population had a mean age of 60.5 years, a mean BMI of 27.0 kg/m2 and 34.7% were female. All patients reported ≥1 AF-related symptoms at baseline and 87.8% presented with AF symptoms ≤ 24 hours in duration. The conversion rate was 46.9% (95% CI: 36.4%, 57.7%), with a median time of 13.7 minutes from the start of the inhalation. A greater proportion of patients were asymptomatic or had improved symptoms following conversion of AF to SR with inhaled flecainide compared to patients whose AF did not convert (92.1% and 45.4%, respectively, p &lt; 0.001). Two patients had CV events that were considered serious (bradycardia and atrial flutter with 1:1 AV conduction). Both CV events were transient (12 and 6 minutes, respectively), required no treatment and resolved without sequelae. Median time to discharge was 2.5 hours for patients whose AF converted to SR with inhaled flecainide and by Day 5 none had experienced AF recurrence. In contrast, 35 (81.4%) patients in the no conversion group had undergone ECV by Day 5. Conclusions: The risk-benefit of orally inhaled flecainide acetate inhalation solution for acute cardioversion of recent onset AF appears favorable and may provide a safe, effective, and convenient first-line therapeutic option for AF conversion.
Abstract 11854: Intensive vs Standard Blood-Pressure Control ni Individuals With Polyvascular Disease
Authors: Hanyuan Shi, Pablo Martinez-Camblor, Mark A Creager, Stanislav Henkin
Journal: Circulation (2022)

Introduction: In the SPRINT trial, intensive blood pressure control reduced all-cause mortality and major adverse cardiovascular events in individuals at high risk for cardiovascular events. However, it is unclear whether individuals with polyvascular disease, compared to individuals without established atherosclerosis, similarly benefit from intensive blood pressure control. Methods: We performed a post-hoc analysis of the SPRINT trial to determine the efficacy of intensive versus standard blood pressure control on the primary composite outcome (myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death); and secondary outcomes (cardiovascular death, myocardial infarction). Individuals were stratified by severity of atherosclerosis: no known atherosclerotic disease (Framingham Risk Score &gt; 15%), subclinical atherosclerosis, symptomatic single-bed atherosclerosis, and symptomatic polyvascular atherosclerosis. Uni- and multivariable Cox regression models were used to compute the crude and adjusted hazard ratios. Interaction between intensive vs standard blood pressure control and atherosclerotic burden was evaluated. Results: In the SPRINT trial, 6,837 individuals had elevated Framingham Risk Score, 128 had subclinical atherosclerosis, 1,207 had symptomatic single-bed atherosclerosis, and 254 had symptomatic polyvascular disease. There was graded increase in risk of primary composite outcome and secondary outcomes with more atherosclerotic burden, even when controlling for differences in baseline characteristics (Figure). There was no interaction among groups between treatment assignment and primary or secondary outcomes. Conclusions: This post-hoc analysis of SPRINT trial demonstrates a higher risk of adverse in patients with escalating atherosclerotic burden. Individuals derive benefit from intensive blood pressure control regardless of burden of atherosclerosis.
Abstract 11089: Comparison of Long-Term Cardiovascular Events of Influenza Patients With versus Without Pre-Existing Cardiovascular Disease in the Infection Treated With Antiviral Agents
Authors: Kyung Teak Park, KI-WOON KANG, Seung Yong Shin, Ho Yeon Won, Hyue Mee Kim, Wang Soo Lee, Sang Wook Kim
Journal: Circulation (2022)

Introduction: The antiviral agents are highly recommended to prevent cardiovascular mortality in patients with pre-existing cardiovascular disease in the pandemic era, but the long-term cardiovascular mortality have not yet been comprehensively characterized in the influenza infection treated with antiviral agents. Hypothesis: This study aimed to compare long-term cardiovascular mortality of influenza patients with versus without pre-existing cardiovascular disease in patients with anti-viral agents. Methods: The data were extracted from the National HealthDatabase from 2001 to 2010, which covers nearly the entire population of South Korea. 865,522 influenza patients treated with anti-viral agents were selected and cardiovascular disease was classified as atrial fibrillation (AF), heart failure (HF), ischemic heart disease (IHD) and 5-year mortality were analyzed using Cox proportional hazard regression model. Results: Of these, 96,433 patients (11.1%, mean age 46) had IHD (86.4%), HF (23.1%) and AF (12.5%) in the influenza infection treated with anti-viral agents. The incidence of IHD was 0.25 per 100-person year in the pre-existing IHD, 0.25 per 100-person year in the pre-existing HF and 0.20 per 100-person year in the pre-existing AF. The incidence of myocarditis was 0.008 per 100-person year in the pre-existing IHD, 0.006 per 100-person year in the pre-existing HF and 0.01 per 100-person year in the pre-existing AF. The incidence of cardiovascular death was 0.49 per 100-person year in the pre-existing IHD, 0.47 per 100-person year in the pre-existing HF and 0.47 per 100-person year in the pre-existing AF. Conclusions: Long-term cardiovascular mortality in influenza patients with pre-existing cardiovascular disease treated with antiviral agents were not significantly different from those without pre-existing cardiovascular disease.